Hydrogel substitutes for tubular somatic organs

ABSTRACT

Substitute somatic organ comprising an insert formed of a tubular knitted textile material and an outer covering bonded to it. The outer covering comprises a hydrogel polymerized about the textile insert in situ.

United States Patent 1191 Wichterle et al.

[4 1 Jan. 28, 1975 I HYDROGEL SUBSTlTUTES- FOR TUBULAR SOMATIC ORGANS[75] lnventors: Otto Wichterle: Karel Kliment; .Iiri

Vacik; Zdenek Ott; Miroslav Stol, all of Praha; Jan Dvorak, Brno, all ofCzechoslovakia [73] Assignee: Ceskoslovenska akademie ved,

Prague, Czechoslovakia [22] Filed: June 21, 1971 [211 Appl. No.: 155,318

Related U.S. Application Data [62] Division of Ser. No. 633,697, April26', 1967,

[52] U.S. Cl. 3/1, 3/DlG. 1,128/334 R [51] int. Cl. A6lf 01/00 [58]Field of Search H 128/334 R, 335. 335.5. 3/1. DIG. 1

[56] References Cited UNITED STATES PATENTS 3,220,960 11/1965 Wichtcrlect a1. 128/334 X 3,272,204 9/1966 Artandi ct al l 128/334 R 3,520,9497/1970 Shepherd et a1. 128/334 R X Primary Examiner-Dalton L. TruluckAttorney, Agent, or Firm-Murray Schaffer 1 1 ABSTRACT Substitute somaticorgan comprising an insert formed of a tubular knitted textile materialand an outer covering bonded to it. The outer covering comprises ahydrogel polymerized about the textile insert in situ.

3 Claims, No Drawings HYDROGEL SUBSTITUTES FOR TUBULAR SOMATIC ORGANSThis application is a division of application Ser. No. 633,697, filedApr. 26, 1967, now abandoned and claim is hereby made to all of theequitable and legal benefits derivable from each.

The invention relates to substitutes for tubular somatic organs,provided with knitted textile reinforcements, and a method of preparingthe same.

Various methods of employing plastics, such as, for example hydrogelsfrom co-polymers of glycol methacrylate and glycol-bis-methacrylate forprosthetic purposes are known. The aforementioned hydrogels have provedoutstanding characteristics for applications in human organisms and,moreover, they possess the additional advantage of having been subjectedfor many years to a great number of tests which have fully proved theirphysiological harmlessness. One of the aims surgical research men havedevoted a great deal of their energy to for a long time, is directedtoward appropriate substitutes for some tubular organs of the humanbody. Thus, for example, for a couple of years there have been testedsubstitutes for various blood vessels where in case of an aneuryism, orforcedly interrupted blood circulation (caused e.g. by a limb trauma) itis necessary to renew the blood circulation through the affected aortaor artery, especially the thoracic or abdominal aortae as well asarteries of the limbs. The substitution can generally be made in threedifferent ways: by auto-implantation, homoeoimplantation, andalloimplantation. The last mentioned mode which consists in applying ablood vessel manufactured from suitable synthetic materials, moreparticularly from a knitted fabric made of physiologicallyunobjectionable synthetic fibres, has been clinically tested and appearsto suit fairly well to the purpose. Nevertheless, not all of theaforementioned materials are fully suitable to be implanted in the humanbody, since the requirements the respective materials have to meet arevery rigorous. These requirements may be set forth as follows:

The material has to be chemically inert, has to possess good mechanicalproperties, must not be physically or chemically attackable by somaticfluids, must not cause inflammatory affections of the tissues, or reactto foreign matter (corpora aliena), must not provoke allergic as well ashypersensitivity symptoms, and must not exhibit cancerigenic effects.Moreover, the tubular organ substitutes must meet some otherrequirements, such as a reduced wall porosity, resistance to chokingwhen bent, and excellent compatibility with somatic liquids. Among mostsuccessful blood vessel substitutes developed as yet there may be citedproducts made of polyacrylonitrile, polyester, polytetrafluorethylenefibres, and a combined collagen-polyester product. Nevertheless, inapplying such blood vessel substitutes considerable problems are faced,of which the most serious is a relative great wall porosity causing astrong hemorrhage upon releasing the full blood pressure thereinto. Thepre-coagulation of blood on the wall of such blood vessel substitutes,which is to overcome said shortcoming, is a time-consuming process anddue to the waste of blood, it can hardly be recommended. I

Other special problems which surgery has to solve in the future consistsin the substitution of urinary, lymphatic, biliary, respiratory ways,the substitution of Fallopian tubes or renewal of a free passagetherethrough,

and the substitution of some tubular organs in ophtalmology,otorhinolaringology, and the like.

An object of the present invention is to provide substitutes for theaforementioned tubular organs, tubular drains, protective bandages, andother medically usable tubes, consisting substantially of a hydrogel onthe basis of hydrophilic polymers, as, for example copolymers,

such as copolymers of monomethacrylate and dimethacrylate of glycols,provided with a textile reinforcement, preferably knitted fromphysiologically harmless synthetic fibers, for example polyester rayon.Such a combination meets all the said requirements and can moreovereasily be prepared, since the textile reinforcement can easily beinterpolymerized into the hydrogel basis so that the finalinterconnection of the two constituents is perfectly intimate, thereinforcement avoiding contact with live tissue and somatic liquidsunless if the latter diffuses through the hydrogel. As hereinbeforereferred to, the textile reinforcement can be interpolymerized into thehydrogel by using some known methods, such as, for example, rotary orcentrifugal casting or impregnating it in a bath followed bypolymerization, or the like. The hydrogel basis with which the textilereinforcement is to be interpolymerized into and with which it forms anintegral body can be prepared in any of suitable processes by using abasic hydrophilic monomer containing one polymerizable double bond ineach molecule, a cross-linking agent may be included which is to behydrophilic, too, but at least soluble in the monomer mixture to such anextent lest it may be separated as a particular phase before theco-polymerization has been finished. The amount of of the cross-linkingagent is to be up to 2 per cent by weight of the basic monomer used. Thecross-linking agent should contain at least two polymerizable doublebonds in each molecule.

A suitable example of the basic monomer and the cross-linking agent isethyleneglycol monomethacrylate and ethyleneglycol-bis-methacrylate,respectively. It is to be understood that other suitable hydrophilicmonomers can be used for the purpose, provided they are hydrophilic,physiologically inert, and have good mechanical properties ifwater-swelled. It is more than probable that in the future some morestable and inert hydrogels will be found, since a large quantity ofthese substances are already known and could as well be prepared in asynthetic way. In lieu of the ethylenglycol monomethacrylate there canbe employed diethylenglycol monomethacrylate or monomethacrylates ofhigher glycolethers, as for example glycerol, or other polyhydricalcohols. Acrylates can be used in these cases as a replacement ofmethacrylate even when they do not possess such a stability in variouschemical and physical conditions. The cross-linking agent can be, forinstance, a mixture of dimethacrylate and trimethacrylate of glycerol orn,n'-methylene-bis-methacrylamide, or the like.

ester filaments, enhances the mechanical properties of the hydrogel, andparticularly acts to reduce the elongation value thereof, the substitutefrom being deformed or damaged. Moreover, it assumes an important task,namely to enable the attachment of the substitute to a live tissue bymeans of stitches without being mechanically impaired. The knittedtextile reinforcement having the same order of elongation value as thehydrogel can be made of polyethylene terepthalate,

fibrous polyacrylonitrile, polytetrafluorethylene, and the like.

A suitable catalyst for starting the polymerizing reaction isdi-isopropyl peroxocarbonate, di-ethyl peroxocarbonate, a mixture ofammonium persulphate or ptassium persulphate and dimethylaminoethylacetate, or a mixture of potassium persulphate and pyrosulphite orsodium, thiosulphate, or the like, accompanied by small quantities oftrace metals, such as copper, iron, or the like; or p-toluensulphic acidand its derivates as well as other known compounds easily liberatingfree radicals.

The deposition of a thicker hydrogel layer may be facilitated byincreasing the viscosity of the mixture to be polymerized by adding aninert polymer thereto, which polymer is soluble in this mixture. Forthis purpose there is suitable a physiologically inert high linearpolymer having a great value of molecular mass, as for example,non-cross-linked polymeric ethyleneglycol methacrylate.

Viscosity can further be increased by simultaneously submerging aplurality of tubular hoses made of textile reinforced knitwork, into acatalyst monomer mixture of which the polymerization rate is known undergiven conditions and which is held in an inert gaseous medium and undersimultaneous viscosity and/or temperature control. When the viscosityattains a sufficient value abrupt gelatination, all the hoses areremoved from the bath at once, and the polymerization is then finishedin an inert gaseous medium, possibly under contributory treatment byinfrared, or ultraviolet rays. The polymerization can be accelerated byprior irradiation of the textile reinforcing material by X-rays, orgama-rays. In this case, however, there exists a danger of prematuregelatination before the knitted hoses have been removed from the monomermixture bath.

EXAMPLE I.

Substitute for a blood vessel (artery) The knitted blood vesselsubstitute made of polyethylene terepthalate and having a diameter of 9millimeters was twice boiled in distilled water, dried in 60 Centrigradewarm air in a drier, and impregnated in a monomer mixture bath containedin a glass cylinder. Thereafter it was transferred into a speciallyadapted glass cylinder communicating with a suitable source of inert gas(carbondioxide, nitrogen, argon or the like), where it was hung on ahook. The surplus monomer mixture was dropped onto the bottom of theglass cylinder. After the interior of the cylinder had been filled upwith the inert gaseous medium, the cylinder wall was being successivelyheated, preferably by hot air at a temperature of about 80 Centigrade.The polymerization proceeded for a time period of about 30 minutes. Thusthe monomer mixture was converted into the gel phase. This procedure wasthen repeated once more, the impregnated hose having been hung by itsother end. Thus a uniform gel deposit on the hose wall was secured.

The monomer mixture was composed of the following constituents: 70 percent by vol. monoethyleneglycol methacrylate monomer containing 0.28 percent by vol. monoethylenglycol-bis-methacrylate, and 30 per cent by vol.distilled glycerol including 0.35 per cent by voldi-isopropylperoxocarbonate as the starting catalyst. Before having been used, themonomer mixture was degasified by means of oil air pump at a temperatureranging between minus 10 to minus Centigrade and a pressure of about 0.1Toor for a period of 5 minutes, whereby the oxygen content inhibitingthe polymerization was removed from the mixture. The 5 blood vesselsubstitute was then several times boiled off in distilled water and putin the sterile physiological solution with an admixture of heparin.Moreover, it is recommended to add suitable antibiotics to the storingsolution, preferably antibiotics having a wide bacteriostatic range,such as, for example, tetracyclinhydro' chloride, or the like. In orderto extend the local effect of the antibiotic agent for the entirerecovery period it is possible to form first a hydrogel layer, to dustit, prior to its reaching the gel point, with a poorly soluble granulardrug, such as tetracycline free base, and then to cover the gelifiedhydrogel with another one in the same way. The antibiotic agent willthen diffuse successively into the adjacent tissue as well as into thecirculating blood.

According to another alternative, a finely pulverized poorly solubleantibiotic agent or any other remedial means is mixed with the solutionof a non-cross-linked polymer, as hereinbefore referred to, as forexample, ethylenglycol monomethacrylate polymer in an alcohol, whereuponthe resulting suspension will be applied to the base hydrogel layer,precipitated by water mist, and finally applied to the top layer ofcatalyst monomer mixture; the polymerization will then proceed ashereinbefore described.

EXAMPLE ll Urethra substitute.

In the procedure corresponding to the described in EXAMPLE 1 anothercomposition of monomer mixture was chosen:

80 per cent monothyleneglycol monomethacrylate, 20 per centdi-ethyleneglycol monomethacrylate (containing 0.26 per centdi-ethyleneglycol-bismethacrylate) and 0.35 per cent di-isopropylperoxocarbonate. The textile reinforcement was boiled off in distilledwater and put in a sterile physiologic solution with an admixture ofsuitable antibiotics.

EXAMPLE [I] Blood vessel substitute.

Onto a horizontally arranged mandrel made of Teflon (RegisteredTrademark) and adapted to be internally heated by means of a resistiveheating device to a temperature of about 60 to 70 Centigrade, a knittedtextile reinforcement having a diameter of 9 millimeters was donnedafter having been previously submerged into the monomer mixture, as inEXAMPLE I, and polymerized under a low speed rotation in an inertgaseous medium for a time period of about 20 to minutes. The procedureis be repeated twice or several times until the desired thickness of thepolymerized layer is attained. The product was then removed from themandrel, boiled off in distilled water and stored under sterileconditions in the physiologic solution.

EXAMPLE IV Blood vessel substitute.

Onto avertically positioned mandrel made of Teflon (R.T.M.) as inEXAMPLE III, a knitted textile reinforcement of polyester rayon wasdonned, whereupon it was helically wrapped up in a thin strip ofpolyethylene foil; into the space between the mandrel and said strip themonomer mixture, as in EXAMPLE II, was then sucked in and the mandrelwas heated by the resistive heating device, as in EXAMPLE III. In thiscase the mandrel was not rotated, but kept in its original verticalposition until the polymerization had been finished. The polyethylenestrip was then wound off after the polymerization, whereupon theresulting substitute was thoroughly rinsed in water, sterilized byboiling and stored in the physiologic solution under sterile conditions.

EXAMPLE V Suction drain for cerebro-spinal liquid.

Into a glass tube of which one extremity was sealed and the interior wasprovided with a special paraffine coating, there was sprayed a freshlyprepared monomer mixture composed of 80 per cent by vol. of a mixture ofmonomers (comprising 90 per cent monoethyleneglycol monomethacrylatecross-linked with 0.32 per cent monoethyleneglycol-bis-methacrylate),per cent by vol. ammonium persulphate in 2 per cent aqueous solution,and 5 per cent by vol. dimethylaminoethyl acetate. The air content wasimmediately blown off by an inert gas, as for example by means of apolyethylene capillary tube and the open end of the capillary tube wassealed in the flame of the Bunsen or any other burner. The glass tubewas then centered and clamped directly on to the shaft of a high speedelectric motor having for example 8.000 r.p.m., and set in rotation. In15 minutes the polymerization was finished.

One of the glass tube ends was cut off so that after melting the thinparaffin layer the polymerized hydrogel tube could be pulled out of theglass tube. Before the lastmentioned operation there was sprayed intothe interior of the hydrogel tube a mixture comprising 30 per cent byvol. monoethyleneglycol monomethacrylate with l per cent cross-linkingadmixture, and 70 per cent by vol. ammonium persulphate in 10 per centaqueous solution so that the interior of the tube might have beenentirely filled up. The glass tube was then heated in an aqueous bath toa temperature of about 60 Centigrade for to minutes. In the interior ofthe glass tube there was produced a finely porous sponge whichafterhaving been removed from the glass tube was several times boiledoff in distilled water. The flow rate of the prepared drain was about1.1 milimeters per minute (when measured at an overpressure of 100milimeters distilled water column). The sterile drain is introduced intoan aperture trepanned in the cranial cavity in the area of the excessiveaccumulation of the cerebro-spinal fluid (as e.g., in case ofencephalitis) while the other end thereof is introduced into the jugularvein where, as well-known, a slight underpressure of about 100millimeters water column prevails. Thus the suction of thecerebro-spinal liquid into the blood circulation can be accomplished.

EXAMPLE VI Substitution of auditory ossicles (mechanical soundtransmission).

A tube having a diameter ranging from 2 to 2.5 milimeters made asdescribed in EXAMPLE V, but without spongious lining, can replace theauditory ossicles in that one of the tube ends is polymerized on to thetympanum while the other end is pulled over the malleus stump. Theelasticity of the hydrogel tube can re-establish the mechanical soundtransmission.

EXAMPLE VII Substitution of oviducts (Fallopian tubes) or renewal offree passage therethrough.

A hydrogel tube as made in Example V of a suitable diameter, preferablyreinforced by a textile knitwork having a perfectly smooth superficialstructure is used as a substitute for the Fallopian tube, enabling thusto attain pregnancy in the indicated cases. The inner surface of thesubstitute, as hereinbefore said, has to be perfectly smooth.

EXAMPLE VIII.

Renewal of free passage through the main lachrymal canal (ductusnasolecrimalis).

A parallell arranged bundle of polyester filaments, preferably crimped,was put in a glass tube of a suitable inner diameter, into which amixture of 30 per cent monoethyleneglycol methacrylate containing 1 percent monoethyleneglycol-bis-methacrylate, and of per cent by vol.ammonium persulphate in 10 per cent aqueous solution, was poured. Oneend of the auxiliary tube extended by a piece of rubber hose pulledthereover was pinched by a clip and the tube was put in a drier heatedto a temperature of about 60 to 70 Centigrade for about 25 to 30minutes. Thus a sponge was produced having the reinforcing bundle ofpolyester filament therein, which sponge could be pulled out of theglass tube. The product was boiled off several times in distilled waterand stored in the physiologic solution.

EXAMPLE IX Ophtalmologic bandage for therapy of separated retina.

An analogous product as described in EXAMPLE VIII was prepared exceptingthat the reinforcement used was made of special crocheted or knittedchain strand which is ladder-proof, that means that after severing toshorter lengths it cannot be unravelled or untwined. The sterilizationwas made as hereinbefore set forth. Before using a desired piece of theblock is cutoff and fastened around the eye bulb whereby the separatedretina can re-occupy its original position and grown thereon.

EXAMPLE X Protective capsule for nerve bundles.

A hydrogel tube of a suitable inner diameter was prepared in thewell-known process of rotary or centrifugal casting, as described inEXAMPLE II, which tube was sterilized and stored in the physiologicsolution. Before application a necessary length of the tube was cut-offand was pulled over the interrupted nerve bundle which was thenconnected with the other end of the broken bundle whereupon the tube waspulled over the joint. Thereby intergrowths with the ambient live tissuecan be prevented, since the hydrogel cannot intergrow through a livetissue. In this manner it is possible to reestablish the nervouscontact, the resilient hydrogel tube showing no obstacle to being bent.

EXAMPLE XI Substitute for a vein.

A hose knitted of polyacrylonitrile crimped filaments was severed to aplurality of 10 to 15 centimetres long sections which were hung on ahorizontal grid made of anticorrosive steel, or a plastic, and arrangedto be easily lifted above the level of the monomer solution. The gridwith the knitted hoses hung therefrom was positioned in a great-diameterglass cylinder supplied permanently with carbondioxide. In the centralportion of the grid there was provided a hole to receive the shaft of anagitator driven from a small-output D.C. electric motor adapted to serveas a simple viscosimeter in that energizing current and/or revolutionscould be recorded.

Alternately, an AC. electric motor having constant revolutions can beemployed for this purpose; in this case there is recorded the inputonly. Moreover, the cylindrical vessel was provided with a highlyresponsive recording thermometer. The monomer mixture cooled to minus 10Centigrade was poured, into the vessel the grid having been placed intothe lowermost of bottom position. The mixture was composed of 60 percent by weight ethyleneglycol monomathacrylate, 19 per cent boiled-offand cooled distilled water free of oxygen, 19 per cent diethyleneglycolmonomethacrylate, one per cent potassium pyrosulphite in 2 per centaqueous solution, one per cent ammonium persulphate in 2 per centaqueous solution, with an admixture of drops of 0.1 per cent copper (I)chloride solution per 250 mililitres of monomer mixture. Air bubbleswere removed by a partial evacuation of the vessel and by repeatedlowering of the grid together with the hoses down to the vessel bottom.Thereafter the viscosimeter was switched,

on. Before this step care is taken taken not to allow the agitatorblades to engage the hung hoses. The procedure was performed until thetemperature rose more rapidly than corresponded to the normal heatsupply from the ambient atmosphere, i.e. until a perceptible change inthe recorded curve course occured, which curve expressed thetemperature/time relationship. Simultaneously, a considerable rise ofviscosity was recorded. In due time before the point of gelatination hadbeen achieved, the grid together with the hung hoses was lifted abovethe liquid level, the surplus amount of the liquid, flowed downwardlyand was removed. By suitably selecting the instant of grid lifting,i.e., within the interval between the rapid polymerization determined bythe abrupt change in the tempeprature/time curve course or a perceptiblerise of viscosity, and the point of gelatination, a desired thickness ofhydrogel layer could be selected. The entire procedure can be repeatedad libitum with a fresh solution and the knitted hoses hung by theirother ends in order to obtain a uniformly thick hydrogel deposit.

The aforementioned interval of lifting was predetermined by a blank testwithout the knitted hoses. The final products were then thoroughlyrinsed in distilled water and stored in the sterile physiologic solutioncontaining an antibiotic agent.

Analogously to the method of producting arterial substitute it ispossible to prepare substitutes for veins. lymphatic ducts, biliaryducts, trachea, acoustic ducts. or the like. In the particular cases acorresponding reinforcing material made from physiologically harmlesssynthetic fibres in form of suitable knitwork has to be selected.

What we claim is:

1. An artificial substitute somatic organ for prosthetic use of a sizeto replace defective body vessels comprising a tubular insert formed ofa porous tubular knitted textile material embedded within a homogeneoushydrogel which is polymerized in situ and surrounds said insert and ispresent within and about the pores thereof and chemically bonded to saidtextile material, said hydrogel comprising a polymer mixture of a firstmonomer selected from the group consisting of glycol monester of acrylicand methacrylic acid having one olefinic double bond in each moleculeand a second monomer comprising a diester of said acrylic andmethacrylic acid having at least two olefinic double bonds in eachmolecule, said second monomer being less than two percent of the totalweight of said combined monomers.

2. The substitute according to claim 1, including a hydrogel layercontaining a biologically active substance intermediate the knittedtextile material and the outer covering, said intermediate layer beingbonded in situ to said textile material.

3. The substitute organ according to claim 1 wherein said reinforcinginsert comprises knitted polyester textile material inert with respectto said monomer mix-

2. The substitute according to claim 1, including a hydrogel layercontaining a biologically active substance intermediate the knittedtextile material and the outer covering, said intermediate layer beingbonded in situ to said textile material.
 3. The substitute organaccording to claim 1 wherein said reinforcing insert comprises knittedpolyester textile material inert with respect to said monomer mixture.